Impaired Platelet Activation in Familial High Density Lipoprotein Deficiency (Tangier Disease)
| Autor: | Thomas Engel, Stephan Rust, Grazyna Herminghaus, Jerzy-Roch Nofer, Udo Seedorf, Horst Bluethmann, Martin Brodde, Gerd Assmann, Eberhard Morgenstern, Beate E. Kehrel |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Platelet membrane glycoprotein Biochemistry Mice Tangier disease Platelet Tangier Disease Mice Knockout biology Chemistry Thrombin Hydrogen-Ion Concentration Middle Aged Adenosine Diphosphate lipids (amino acids peptides and proteins) Collagen GPVI ATP Binding Cassette Transporter 1 Blood Platelets congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Antigens Differentiation Myelomonocytic Phosphatidylserines Platelet Membrane Glycoproteins Cytoplasmic Granules Antigens CD Internal medicine medicine Animals Humans Platelet activation Molecular Biology Aged Tetraspanin 30 Fibrinogen Lysosome-Associated Membrane Glycoproteins nutritional and metabolic diseases Fibrinogen binding Cell Biology Platelet Activation medicine.disease Mice Inbred C57BL Microscopy Electron Endocrinology ABCA1 biology.protein ATP-Binding Cassette Transporters Lysosomes Cell Adhesion Molecules |
| Zdroj: | Journal of Biological Chemistry. 279:34032-34037 |
| ISSN: | 0021-9258 |
| Popis: | ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, alpha2beta1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|